Malignant gliomas are highly lethal tumors that resist conventional therapies. Tumor invasion into normal brain is a critical contributor to treatment failure. Despite the importance of tumor invasion, little of the biochemical pathways regulating invasion are recognized. Secreted protein, acidic and rich in cysteine (SPARC) - also known as osteonectin - is a protein frequently overexpressed in gliomas at sites of invasion. We have recently demonstrated in a gene expression study of older glioblastoma patients that SPARC expression contributes to poor outcome. In glioma cell lines, we and others have shown that SPARC expression induces invasion both in vitro and in vivo with increased matrix metalloproteinase (MMP) expression. Additionally, we have demonstrated that SPARC expression increases cellular survival under stress with increased Akt activation. Thus, SPARC may augment glioma invasion through multiple mechanisms. In our current studies, we will study the biochemical pathways initiated in response to SPARC and determine the impact of targeting SPARC expression. In Specific Aim 1, we will define the contribution of Akt activation to SPARC-induced MMP expression and tumor invasion. In Aim 2, we will examine the activating kinases upstream to Akt in the SPARC signaling cascade with a focus on non-receptor tyrosine kinases. In Aim 3, we will define the impact of targeting SPARC expression with RNAi on invasion both in vitro and in vivo. These studies will contribute to the understanding of the regulation of glioma invasion and provide the basis of novel targeted therapies for gliomas.